The .beta.-adrenergic receptor blocking agents comprise an important group of approved therapeutic agents. They have the common pharmacological property of blocking the action of agonists of .beta.-adrenergic receptor sites in that they compete with the agonists for receptor sites. Various physiological responses, characteristic of the tissue which is involved, occur as a result of blocking of the receptor site. Beta-adrenergic blocking agents have a variety of pharmacokinetic properties, some of which may influence side effects. Commonly, these agents are administered to patients suffering from ischemic heart disease or myocardial infarction for the purpose of reducing the work conducted by the heart, namely heart rate and contractile force. Reducing heart work reduces oxygen demand and may in fact, increase oxygen supply. Reducing the work required of the heart can thereby minimize or prevent further tissue damage and can relieve the pain of angina pectoris.
The use of .beta.-adrenergic receptor blocking agents to decrease myocardial oxygen requirements and control dysrhythmia after acute myocardial infarction has, however, been somewhat limited in view of the potential for producing long-lasting cardiac depression. It has therefore been suggested (Erhardt, et al, J Med Chem, 1982, Vol. 25, pp 1402-1407) that .beta.-adrenergic blocking agents having an ultrashort duration of action could minimize or eliminate this limitation. Such agents could be administered by intravenous infusion to rapidly obtain desired levels of .beta.-adrenergic blockade; allow rapid adjustment of blockade as might be required; and reduce the risk of resultant long-lasting cardiac depression since the effects of the agent would rapidly dissipate upon the termination of the infusion.
As described in the Erhardt, et al publication, supra as well as publications by Zaroslinski, et al, Life Sciences, Vol. 31, pp 899-907, 1982 and Erhardt, et al, J Med Chem, Vol 25, 1982, pp 1408-1412, certain compounds containing ester functions have been found to possess .beta.-adrenergic blocking action of relatively short duration of action in vivo. Consequently, these compounds minimize the disadvantages of previous .beta.-blocking agents. The ester groups in these compounds are however, somewhat unstable in aqueous solutions such as those used for intravenous administration. As a consequence, such solutions have a relatively short shelf life. Pharmaceutical compositions of short-acting .beta.-blocking agents which are stable in solution and therefore have a relatively long shelf life are desirable since they would facilitate storage and commercial distribution.